{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T20:32:09Z","timestamp":1773952329735,"version":"3.50.1"},"reference-count":48,"publisher":"Elsevier BV","issue":"3","license":[{"start":{"date-parts":[[2008,1,1]],"date-time":"2008-01-01T00:00:00Z","timestamp":1199145600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2008,1,1]],"date-time":"2008-01-01T00:00:00Z","timestamp":1199145600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"}],"content-domain":{"domain":["clinicalkey.com","clinicalkey.com.au","clinicalkey.es","clinicalkey.fr","clinicalkey.jp","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Toxicology"],"published-print":{"date-parts":[[2008,1]]},"DOI":"10.1016\/j.tox.2007.10.011","type":"journal-article","created":{"date-parts":[[2007,10,24]],"date-time":"2007-10-24T07:17:19Z","timestamp":1193210239000},"page":"249-260","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":49,"title":["Investigation of the effect of a panel of model hepatotoxins on the Nrf2-Keap1 defence response pathway in CD-1 mice"],"prefix":"10.1016","volume":"243","author":[{"given":"Laura E.","family":"Randle","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chris E.P.","family":"Goldring","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Craig A.","family":"Benson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter N.","family":"Metcalfe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neil R.","family":"Kitteringham","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"B. Kevin","family":"Park","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dominic P.","family":"Williams","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"78","reference":[{"key":"10.1016\/j.tox.2007.10.011_bib1","doi-asserted-by":"crossref","first-page":"26071","DOI":"10.1074\/jbc.274.37.26071","article-title":"Nrf2, a Cap\u2019n\u2019Collar transcription factor, regulates induction of the heme oxygenase-1 gene","volume":"274","author":"Alam","year":"1999","journal-title":"J. Biol. Chem."},{"key":"10.1016\/j.tox.2007.10.011_bib2","doi-asserted-by":"crossref","DOI":"10.1074\/jbc.M307633200","article-title":"Phosphorylation of Nrf2S40 by PKC in response to antioxidants leads to the release of Nrf2 from INrf2 but not required for Nrf2 stabilization\/accumulation in the nucleus and transcriptional activation of ARE-mediated NQO1 gene expression","author":"Bloom","year":"2003","journal-title":"J. Biol. Chem."},{"key":"10.1016\/j.tox.2007.10.011_bib3","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1042\/bj1040095","article-title":"Enzyme-catalysed conjugations of glutathione with unsaturated compounds","volume":"104","author":"Boyland","year":"1967","journal-title":"Biochem. J."},{"key":"10.1016\/j.tox.2007.10.011_bib4","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1006\/taap.1995.1207","article-title":"Induction of phase I and phase II drug-metabolizing enzyme mRNA, protein, and activity by BHA, ethoxyquin, and oltipraz","volume":"135","author":"Buetler","year":"1995","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"10.1016\/j.tox.2007.10.011_bib5","first-page":"225","article-title":"Liver glutathione depletion induced by bromobenzene, idobenzene, and diethylmaleate poisoning and its relation to lipid peroxidation","volume":"118","author":"Casini","year":"1985","journal-title":"Am. J. Pathol."},{"key":"10.1016\/j.tox.2007.10.011_bib6","doi-asserted-by":"crossref","first-page":"12731","DOI":"10.1073\/pnas.96.22.12731","article-title":"Nrf2 is essential for protection against acute pulmonary injury in mice","volume":"96","author":"Chan","year":"1999","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"10.1016\/j.tox.2007.10.011_bib7","doi-asserted-by":"crossref","first-page":"13943","DOI":"10.1073\/pnas.93.24.13943","article-title":"Nrf2, a member of the NFE2 family of transcription factors, is not essential for murine erythropoiesis, growth, and development","volume":"93","author":"Chan","year":"1996","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"10.1016\/j.tox.2007.10.011_bib8","doi-asserted-by":"crossref","first-page":"7280","DOI":"10.1073\/pnas.0501475102","article-title":"Utility of siRNA against Keap1 as a strategy to stimulate a cancer chemopreventive phenotype","volume":"102","author":"Devling","year":"2005","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"10.1016\/j.tox.2007.10.011_bib9","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.1093\/nar\/11.5.1475","article-title":"Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei","volume":"11","author":"Dignam","year":"1983","journal-title":"Nucleic Acids Res."},{"key":"10.1016\/j.tox.2007.10.011_bib10","doi-asserted-by":"crossref","first-page":"11908","DOI":"10.1073\/pnas.172398899","article-title":"Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants","volume":"99","author":"Dinkova-Kostova","year":"2002","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"10.1016\/j.tox.2007.10.011_bib11","doi-asserted-by":"crossref","first-page":"3404","DOI":"10.1073\/pnas.051632198","article-title":"Potency of Michael reaction acceptors as inducers of enzymes that protect against carcinogenesis depends on their reactivity with sulfhydryl groups","volume":"98","author":"Dinkova-Kostova","year":"2001","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"10.1016\/j.tox.2007.10.011_bib12","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1093\/toxsci\/59.1.169","article-title":"High sensitivity of Nrf2 knockout mice to acetaminophen hepatotoxicity associated with decreased expression of ARE-regulated drug metabolizing enzymes and antioxidant genes","volume":"59","author":"Enomoto","year":"2001","journal-title":"Toxicol. Sci."},{"key":"10.1016\/j.tox.2007.10.011_bib13","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1021\/tx034170b","article-title":"Drug-protein adducts: an industry perspective on minimizing the potential for drug bioactivation in drug discovery and development","volume":"17","author":"Evans","year":"2004","journal-title":"Chem. Res. Toxicol."},{"key":"10.1016\/j.tox.2007.10.011_bib14","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1002\/hep.20183","article-title":"Activation of hepatic Nrf2 in vivo by acetaminophen in CD-1 mice","volume":"39","author":"Goldring","year":"2004","journal-title":"Hepatology"},{"key":"10.1016\/j.tox.2007.10.011_bib15","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1081\/DMR-120034148","article-title":"Clinical perspectives on xenobiotic-induced hepatotoxicity","volume":"36","author":"Gunawan","year":"2004","journal-title":"Drug Metab. Rev."},{"key":"10.1016\/j.tox.2007.10.011_bib16","doi-asserted-by":"crossref","first-page":"2899","DOI":"10.1038\/sj.onc.1208615","article-title":"The p53 pathway: positive and negative feedback loops","volume":"24","author":"Harris","year":"2005","journal-title":"Oncogene"},{"key":"10.1016\/j.tox.2007.10.011_bib17","doi-asserted-by":"crossref","first-page":"31768","DOI":"10.1074\/jbc.M503346200","article-title":"Specific patterns of electrophile adduction trigger Keap1 ubiquitination and Nrf2 activation","volume":"280","author":"Hong","year":"2005","journal-title":"J. Biol. Chem."},{"key":"10.1016\/j.tox.2007.10.011_bib18","doi-asserted-by":"crossref","first-page":"42769","DOI":"10.1074\/jbc.M206911200","article-title":"Phosphorylation of Nrf2 at Ser-40 by protein kinase C regulates antioxidant response element-mediated transcription","volume":"277","author":"Huang","year":"2002","journal-title":"J. Biol. Chem."},{"key":"10.1016\/j.tox.2007.10.011_bib19","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1006\/bbrc.1997.6943","article-title":"An Nrf2\/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements","volume":"236","author":"Itoh","year":"1997","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"10.1016\/j.tox.2007.10.011_bib20","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1101\/gad.13.1.76","article-title":"Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain","volume":"13","author":"Itoh","year":"1999","journal-title":"Genes Dev."},{"key":"10.1016\/j.tox.2007.10.011_bib21","doi-asserted-by":"crossref","DOI":"10.1074\/jbc.M502083200","article-title":"Nuclear import and export signals in control of NRF2","author":"Jain","year":"2005","journal-title":"J. Biol. Chem."},{"key":"10.1016\/j.tox.2007.10.011_bib22","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1053\/jhep.2000.9602","article-title":"Hepatocellular response to chemical stress in CD-1 mice: induction of early genes and gamma-glutamylcysteine synthetase","volume":"32","author":"Kitteringham","year":"2000","journal-title":"Hepatology"},{"key":"10.1016\/j.tox.2007.10.011_bib23","doi-asserted-by":"crossref","first-page":"7130","DOI":"10.1128\/MCB.24.16.7130-7139.2004","article-title":"Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2","volume":"24","author":"Kobayashi","year":"2004","journal-title":"Mol. Cell. Biol."},{"key":"10.1016\/j.tox.2007.10.011_bib24","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1081\/DMR-120000652","article-title":"Induction of xenobiotic enzymes by the map kinase pathway and the antioxidant or electrophile response element (ARE\/EpRE)","volume":"33","author":"Kong","year":"2001","journal-title":"Drug Metab. Rev."},{"key":"10.1016\/j.tox.2007.10.011_bib25","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1021\/tx00047a019","article-title":"Investigations of glutathione conjugation in vitro by 1H NMR spectroscopy. Uncatalyzed and glutathione transferase-catalyzed reactions","volume":"8","author":"Kubal","year":"1995","journal-title":"Chem. Res. Toxicol."},{"key":"10.1016\/j.tox.2007.10.011_bib26","first-page":"139","article-title":"An important role of Nrf2-ARE pathway in the cellular defence mechanism","volume":"37","author":"Lee","year":"2004","journal-title":"J. Biochem. Mol. Biol."},{"key":"10.1016\/j.tox.2007.10.011_bib27","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1056\/NEJMra021844","article-title":"Drug-induced hepatotoxicity","volume":"349","author":"Lee","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"10.1016\/j.tox.2007.10.011_bib28","article-title":"NRF2 possesses a Redox-insensitive nuclear export signal overlapping with the leucine zipper motif","author":"Li","year":"2005","journal-title":"J. Biol. Chem."},{"key":"10.1016\/j.tox.2007.10.011_bib29","doi-asserted-by":"crossref","first-page":"1586","DOI":"10.1016\/j.lfs.2007.01.034","article-title":"Extract of Ginkgo biloba induces phase 2 genes through Keap1-Nrf2-ARE signaling pathway","volume":"80","author":"Liu","year":"2007","journal-title":"Life Sci."},{"key":"10.1016\/j.tox.2007.10.011_bib30","doi-asserted-by":"crossref","first-page":"S83","DOI":"10.1097\/01.mcg.0000155548.91524.6e","article-title":"Drug-induced hepatotoxicity: 2005","volume":"39","author":"Maddrey","year":"2005","journal-title":"J. Clin. Gastroenterol."},{"key":"10.1016\/j.tox.2007.10.011_bib31","doi-asserted-by":"crossref","first-page":"21592","DOI":"10.1074\/jbc.M300931200","article-title":"Keap1-dependent proteasomal degradation of transcription factor Nrf2 contributes to the negative regulation of antioxidant response element-driven gene expression","volume":"278","author":"McMahon","year":"2003","journal-title":"J. Biol. Chem."},{"key":"10.1016\/j.tox.2007.10.011_bib32","doi-asserted-by":"crossref","first-page":"3499S","DOI":"10.1093\/jn\/134.12.3499S","article-title":"Transcription factor Nrf2 is essential for induction of NAD(P)H:quinone oxidoreductase 1, glutathione S-transferases, and glutamate cysteine ligase by broccoli seeds and isothiocyanates","volume":"134","author":"McWalter","year":"2004","journal-title":"J. Nutr."},{"key":"10.1016\/j.tox.2007.10.011_bib33","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1146\/annurev.pharmtox.45.120403.100058","article-title":"The role of metabolic activation in drug-induced hepatotoxcity","volume":"45","author":"Park","year":"2005","journal-title":"Annu. Rev. Phrmacol. Toxicol."},{"key":"10.1016\/j.tox.2007.10.011_bib34","series-title":"Proceedings of the 9th European ISSX Meeting","first-page":"166","article-title":"Adrenergic modulation of chemical-induced hepatotoxicity","author":"Randle","year":"2006"},{"key":"10.1016\/j.tox.2007.10.011_bib35","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/0163-7258(89)90050-8","article-title":"Mechanisms of carbon tetrachloride toxicity","volume":"43","author":"Recknagel","year":"1989","journal-title":"Pharmacol. Ther."},{"key":"10.1016\/j.tox.2007.10.011_bib36","first-page":"5636","article-title":"NADPH oxidase activity is essential for Keap1\/Nrf2-mediated induction of GCLC in response to 2-indol-3-yl-methylenequinuclidin-3-ols","volume":"63","author":"Sekhar","year":"2003","journal-title":"Cancer Res."},{"key":"10.1016\/j.tox.2007.10.011_bib37","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/S0026-895X(25)15072-4","article-title":"Free radicals in vivo. Covalent binding to lipids","volume":"26","author":"Smith","year":"1984","journal-title":"Mol. Pharmacol."},{"key":"10.1016\/j.tox.2007.10.011_bib38","doi-asserted-by":"crossref","first-page":"1690","DOI":"10.1016\/j.freeradbiomed.2007.02.017","article-title":"Action of Nrf2 and Keap1 in ARE-mediated NQO1 expression by quercetin","volume":"42","author":"Tanigawa","year":"2007","journal-title":"Free Radic. Biol. Med."},{"key":"10.1016\/j.tox.2007.10.011_bib39","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1002\/hep.20094","article-title":"Subliminal Fas stimulation increases the hepatotoxicity of acetaminophen and bromobenzene in mice","volume":"39","author":"Tinel","year":"2004","journal-title":"Hepatology"},{"key":"10.1016\/j.tox.2007.10.011_bib40","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1007\/BF00755791","article-title":"A microtiter plate assay for total glutathione and glutathione disulfide contents in cultured\/isolated cells: performance study of a new miniaturized protocol","volume":"10","author":"Vandeputte","year":"1994","journal-title":"Cell Biol. Toxicol."},{"key":"10.1016\/j.tox.2007.10.011_bib41","doi-asserted-by":"crossref","first-page":"3145","DOI":"10.1038\/sj.onc.1202237","article-title":"Nrf2 and Nrf1 in association with Jun proteins regulate antioxidant response element-mediated expression and coordinated induction of genes encoding detoxifying enzymes","volume":"17","author":"Venugopal","year":"1998","journal-title":"Oncogene"},{"key":"10.1016\/j.tox.2007.10.011_bib42","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1038\/ng1248","article-title":"Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation","volume":"35","author":"Wakabayashi","year":"2003","journal-title":"Nat. Genet."},{"key":"10.1016\/j.tox.2007.10.011_bib43","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.tox.2006.08.014","article-title":"Dynamic changes of heme oxygenase-1 and carbon monoxide production in acute liver injury induced by carbon tetrachloride in rats","volume":"228","author":"Wen","year":"2006","journal-title":"Toxicology"},{"key":"10.1016\/j.tox.2007.10.011_bib44","doi-asserted-by":"crossref","first-page":"33627","DOI":"10.1074\/jbc.274.47.33627","article-title":"Regulation of gamma-glutamylcysteine synthetase subunit gene expression by the transcription factor Nrf2","volume":"274","author":"Wild","year":"1999","journal-title":"J. Biol. Chem."},{"key":"10.1016\/j.tox.2007.10.011_bib45","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1124\/jpet.107.125302","article-title":"The metabolism and toxicity of furosemide in the Wistar rat and CD-1 mouse: a chemical and biochemical definition of the toxicophore","volume":"322","author":"Williams","year":"2007","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"10.1016\/j.tox.2007.10.011_bib46","doi-asserted-by":"crossref","first-page":"8749","DOI":"10.1074\/jbc.M610790200","article-title":"Nrf2-Keap1 signaling pathway regulates human UGT1A1 expression in vitro and in transgenic UGT1 mice","volume":"282","author":"Yueh","year":"2007","journal-title":"J. Biol. Chem."},{"key":"10.1016\/j.tox.2007.10.011_bib47","doi-asserted-by":"crossref","first-page":"10941","DOI":"10.1128\/MCB.24.24.10941-10953.2004","article-title":"Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex","volume":"24","author":"Zhang","year":"2004","journal-title":"Mol. Cell. Biol."},{"key":"10.1016\/j.tox.2007.10.011_bib48","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1179\/135100007X162266","article-title":"Submicromolar concentrations of 4-hydroxynonenal induce glutamate cysteine ligase expression in HBE1 cells","volume":"12","author":"Zhang","year":"2007","journal-title":"Redox. Rep."}],"container-title":["Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0300483X07006816?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0300483X07006816?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T22:59:40Z","timestamp":1759532380000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0300483X07006816"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,1]]},"references-count":48,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2008,1]]}},"alternative-id":["S0300483X07006816"],"URL":"https:\/\/doi.org\/10.1016\/j.tox.2007.10.011","relation":{},"ISSN":["0300-483X"],"issn-type":[{"value":"0300-483X","type":"print"}],"subject":[],"published":{"date-parts":[[2008,1]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Investigation of the effect of a panel of model hepatotoxins on the Nrf2-Keap1 defence response pathway in CD-1 mice","name":"articletitle","label":"Article Title"},{"value":"Toxicology","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.tox.2007.10.011","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"Copyright \u00a9 2007 Elsevier Ireland Ltd. All rights reserved.","name":"copyright","label":"Copyright"}]}}